Neurodegenerative illnesses and neurological disorders constitute a serious social and economic problem. Clear examples are represented by senile dementia, Alzheimer, Huntington, and the one associated to the AIDS virus, as well as the neurodegeneration caused by ischemia associated to a cerebrovascular accident. In spite of the seriousness of the problem, the pharmacological arsenal to fight, prevent, and/or decrease its symptoms and progress, is surprisingly limited.
Though the biological mechanisms that lead to the neurodegeneration are not clearly established, in many neurodegenerative illnesses, such as amiotrophic lateral sclerosis, dementia associated to AIDS and to Alzheimer, the presence of high and chronic levels of the L-glutamate excitotoxic neurotransmitter (1–3), has been observed in the cerebral parenchyma. This neurotransmitter has also been involved in the etiology of neurological disorders such as cerebral ischemia (4). The glutamate activates membrane receptors that have an ionic channel activity (ionotropic receptors) or that transduce the signal through G proteins (metabotropic receptors) (5). The ionotropic receptors, especially those of the NNDA type [N-methyl-D-aspartate activated glutamate receptors (NMDA)], have been involved in the glutamatergic neurodegeneration due to their high Ca2+ ion permeability (1–5). The proposed molecular mechanism indicates that high and chronic levels of glutamate cause a prolonged activation (hyperactivation) of the NMDA receptor that “overloads” the neurones with Ca2+ ions, triggering off the massive activation and excessive intracellular cascades that, inevitably lead to neuronal death (1–8). In fact, it has been described that antagonists of this receptor are capable of preventing the glutamate neurotoxicity (8,9). From what is expounded it can be deduced, that a strategy for preventing or decreasing the neurodegeneration is to control the functional activity of this ionotropic receptor, especially, under conditions in which a high pathology of the glutamate levels exist.
In spite of the advance made in the past few years, potent, selective and toxicity-free neuroprotectors have not yet been developed. Up to the moment, a large part of the effort has been focused, towards the development of competitive inhibitors that recognise the glutamaterglcal receptors of the central nervous system (1,2). For example, an important effort has been made to develop competitive and non competitive antagonists of glutamate and/or glycine [a coagonist that participates in the activation of the NMDA type glutamate]. These molecules, though powerful neuroprotectors, present important secondary effects, such as cognitive anomalies, that limit their clinical use (10–12). The main disadvantage of using competitive and non competitive antagonist is that they interact with their receptors, non specifically inhibiting the neurotransmission, and affecting both the pathological activity of the glutamate and its physiological activity (13). A strategy to overcome this therapeutic obstacle would be to use non competitive and/or acompetitive antagonists that preferably join the agonists-receptor complex. The most important advantage of using this type of antagonists is that these agents mainly act on hyperactivated receptors (pathological receptors), showing a marginal interaction over receptors that perform on rapid excitory neurotransmission processes (physiological receptors) (13). This preferred activity over the “pathological” receptors makes these types of antagonists valued as promising therapeutic agents to prevent the neurodeceneration (13–18). Molecules such as phencyclidine and dizolcipine are powerful acompetitive antagonists of the NMDA receptor that act as efficient in vitro neuroprotectors (12–18). However, their clinical use is questioned due to the psycotomimetic effects (13).